ORGANIC LETTERS
Nucleophilic Displacement at Benzhydryl Centers: Asymmetric Synthesis of 1,1-Diarylalkyl Derivatives
2004 Vol. 6, No. 1 111-114
Yuri Bolshan,†,‡ Cheng-yi Chen,§ Jennifer R. Chilenski,§ Francis Gosselin,† David J. Mathre,§ Paul D. O’Shea,*,† Ame´lie Roy,† and Richard D. Tillyer§ Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-DorVal, Que´ bec, H9R 4P8, Canada, and Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA
[email protected] Received November 5, 2003
ABSTRACT
Activation of substituted 1,1-diarylmethanols as their corresponding toluenesulfonates and subsequent displacement with a range of carbon, nitrogen, oxygen, and sulfur nucleophiles proceeds in 81−96% yield. Enantiomerically enriched diarylmethanols 8a−c were activated and displaced with pyridine acetate enolate with complete stereochemical inversion at carbon to yield 1,1-diarylalkyl derivatives 10a−c without loss of optical purity.
Substituted 1,1-diarylalkyl derivatives form the core structure of a number of pharmacologically active compounds. For example, the 1,1-diarylalkyl structural element is found in compounds with reported activity as antimuscarinics,1 antidepressants,2 and endothelin antagonists.3 As such, there is a need for practical synthetic methodologies for the preparation of a wide variety of compounds of this type, especially in optically pure form. The asymmetric synthesis of the 1,1-diarylalkyl skeleton poses some interesting challenges. Reported syntheses include methods based on asymmetric epoxidation of a trisubstituted alkene or chiral sulfur-ylide,4 catalytic asym-
metric C-H insertion of rhodium carbenoids derived from aryl diazoacetates into cyclohexadienes,5 aryl cuprate addition to chiral cyclopropane dicarboxylates,6 and diastereoselective and enantioselective conjugate addition of organometallic reagents to cinnamate derivatives7 (Scheme 1).
Scheme 1. Synthetic Approaches to 1,1-Diarylalkyl Derivatives
†
Merck Frosst Centre for Therapeutic Research. Merck Frosst undergraduate coop student from the University of Waterloo, Ontario, Canada. § Merck Research Laboratories, Rahway. (1) Nilvebrant, L.; Andersson, K.-E.; Gillberg, P.-G.; Stahl, M.; Sparf, B. Eur. J. Pharmacol. 1997, 327, 195. (2) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem. 1984, 27, 1508. (3) Astles, P. C.; Brown, T. J.; Halley, F.; Handscombe, C. M.; Harris, N. V.; Majid, T. N.; McCarthy, C.; McLay, I. M.; Morley, A.; Porter, B.; Roach, A. G.; Sargent, C.; Smith, C.; Walsh, R. J. A. J. Med. Chem. 2000, 43, 900. ‡
10.1021/ol0361655 CCC: $27.50 Published on Web 12/13/2003
© 2004 American Chemical Society
Our interest in this structural motif originated from the discovery of CDP-8408 and compound I9 as potent and
selective phosphodiesterase IV (PDE-IV) inhibitors (Figure 1). Selective PDE-IV inhibitors are currently under investiga-
for the rapid synthesis of 1,1-diarylalkyl derivatives in both racemic and enantioenriched form. We initially focused our efforts on developing a suitable electrophile for alkylation by the lithium enolate of ethyl 4-pyridyl acetate using 1,1-diarylmethanols such as 1 (Scheme 2). Although racemic chloride and bromide derivatives 2a
Scheme 2 a
Figure 1. PDE-IV Inhibitors.
tion as potential therapeutic agents for the treatment of asthma and chronic obstructive pulmonary disease (COPD), and a number of these compounds have entered clinical trials.10 We sought to develop a practical methodology that would allow access to a large number of racemic analogues of I that also had the potential to be developed into an asymmetric synthesis. We reasoned that a protocol based on nucleophilic displacement of suitably activated benzhydryl alcohol derivatives could provide access to a wide variety of 1,1-diaryl substituted products in a minimal number of steps from readily available, simple starting materials. With the exception of bromides and chlorides, the synthetic utility of activated benzhydryl derivatives has received scant attention in the literature. This may be a consequence of the general expectation that diaryl-substituted electrophiles may be exceedingly prone to ionization, racemization, and decomposition and therefore not synthetically useful. In this communication, we describe our efforts to identify a suitable leaving group and develop a synthetic methodology (4) (a) Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223. (b) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T.; Angew. Chem., Int. Ed. 2003, 42, 3274. (5) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 2, 233. (6) Corey, E. J.; Gant, G. T. Tetrahedron Lett. 1994, 35, 5373. (7) (a) Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. M.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1998, 63, 3120. (b) Xu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron: Asymmetry 1998, 9, 1651. (c) Asano, Y.; Iida A.; Tomioka, K. Chem. Pharm. Bull. 1998, 46, 184. (d) Houpis, I. N.; Lee, J.; Dorziotis, I.; Molina, A.; Reamer, B.; Volante, R. P.; Reider, P. J. Tetrahedron 1998, 54, 1185. (8) Alexander, R. P.; Warrellow, G. J.; Eaton, M. A. W.; Boyd, E. C.; Head, J. C.; Porter, J. R.; Brown, J. A.; Reuberson, J. T.; Hutchinson, B.; Turner, P.; Boyce, B.; Barnes, D.; Mason, B.; Cannell, A.; Taylor, R. J.; Zomaya, A.; Millican, A.; Leonard, J.; Morphy, R.; Wales, M.; Perry, M.; Allen, R. A.; Gozzard, N.; Hughes, B.; Higgs, G. Bioorg. Med. Chem. Lett. 2002, 12, 1451. (9) Guay, D.; Hamel, P.; Blouin, M.; Brideau, C.; Chan, C. C.; Chauret, N.; Ducharme, Y.; Huang, Z.; Girard, M.; Jones, T. R.; Laliberte´, F.; Masson, P.; McAuliffe, M.; Piechuta, H.; Silva, J.; Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1457. (10) (a) Huang, Z.; Ducharme, Y.; MacDonald, D.; Robichaud, A. Curr. Opin. Chem. Biol. 2001, 5, 432. (b) Martin, T. J. IDrugs 2001, 4, 312. (c) Nell, H.; Louw, C.; Leichtl, S.; Rathgeb, F.; Neuhauser, M.; Bardin, P. G. Am. J. Respir. Crit. Care Med. 2000, 161, A200. (d) Timmer, W.; Leclerc, V.; Birraux, G.; Neuhauser, M.; Hatzelmann, A.; Bethke, T.; Wurst, W. Am. J. Respir. Crit. Care Med. 2000, 161, A505. 112
a Conditions: (a) Activation. (b) Ethyl 4-pyridylacetate, LiN(SiMe3)2, THF, DMPU, -40 °C.
were previously demonstrated to be reasonably good substrates for nucleophilic displacement with pyridinyl enolates,9,11 our attempts to prepare chlorides and bromides from the corresponding optically enriched alcohols were unsuccessful because of extensive racemization during their formation. Other activating groups were thus screened. Phosphate leaving groups 2b (R) Et, i-Pr) could be readily prepared but were unreactive toward lithium enolates. Attempted preparation of methanesulfonate 2c using methanesulfonyl chloride led exclusively to the corresponding chloride, while use of methanesulfonic anhydride led to decomposition of the starting benzhydrol. Similarly, attempts
Table 1. Displacement of Benzhydrol Toluenesulfonates with Lithium Enolate of Ethyl 4-Pyridyl Acetatea
entry
Ar
product
yield (%)
1 2 3 4 5 6 7 8 9 10 11
4-MeOC6H4 3-MeOC6H4 2-MeOC6H4 3,5-MeOC6H3 C6H5 4-CF3C6H4 3-CF3C6H4 2-CF3C6H4 3,5-CF3C6H3 3,4-MeOC6H3 3,4-HCF2OC6H3
5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k
68 73 15 28 76 74 68
